We have chosen mouse models for three devastating and common human neurological diseases—multiple sclerosis, Alzheimer's disease, and Parkinson's disease. These models provide a well-delimited workspace for our collaboration and maintain firm linkage to the two active Human BIRN test-beds and the BIRN-CC. All three diseases have mixed genetic and environmental etiologies and are sufficiently complex to be challenging from a bioinformatics perspective.
Parkinson's Disease, the Alpha Synuclein Mouse Model
The project efforts are focused on the development and application of correlated imaging approaches (confocal and electron microscopy, in vivo microscopic MRI) to Parkinson's disease (PD)—applied first to recently generated transgenic animal models of PD. Knowledge gained from this project will facilitate the assessment of neuropathologies and effectiveness of possible chemotherapeutic treatments for PD.
The overall goals for this project are to:
1. Characterize the phenotypic differences between transgenic alpha synuclein and wildtype mice at three levels:
High resolution distribution maps of molecular constituents
2. Integrate multi-scale data into the BIRN3. Establish collaborations with other groups and bring additional PD models for comparison
Multiple Sclerosis, the EAE Mouse Model
The pathology of Experimental Autoimmune Encephalomyelitis (EAE) is characterized by lymphocytic and mononuclear cell infiltration of the CNS, an increase in blood-brain barrier permeability, astrocytic hypertrophy, and often demyelination, all of which contribute to the observed clinical expression of disease, imbalance, and paralysis. This particular mouse model of EAE exhibits lesions in the C57BL/6 mouse in the brain within 45 days of the antigenic challenge. Because the clinical and pathological aspects of this disease bear significant similarities to multiple sclerosis (MS) it is a valuable model of that human demyelinating disease.
The brains of these mice are visualized using Magnetic Resonance Microscopy (MRM), histology, and immunohistochemistry. Lesions in these brains have been identified using these methods. The data are reconstructed into 3D volumes and registered into a common and defined coordinate system and atlased. This atlased information serves as a valuable tool for the collection and comparison of data in this model of MS as well as for future investigation of potential treatments.
Alzheimer's Disease, Tet-off APP Transgenic Mouse Model
Alzheimer's disease is thought to arise from the accumulation of a small peptide termed amyloid- b that is normally found in healthy individuals, but is abnormally abundant in the brains of AD patients. The Ab peptide aggregates into extracellular lesions or amyloid plaques that are found throughout the hippocampus and cortex of affected individuals. Both amyloid pathology and the cognitive decline associated with AD can be recreated in transgenic mouse models for the disease. Mice overexpressing the human amyloid precursor protein (APP) with mutations identified from families with inherited AD generate high levels of Ab and form amyloid plaques similar to those used found in the brains of patients with AD.
The mouse BIRN will examine a transgenic mouse model for AD in which the expression of APP can be controlled with antibiotic treatment. We anticipate that this controllable transgenic mouse model can be used with MRI and the other methods employed by collaborators in the mouse BIRN to study the long-term kinetics of amyloid lesions in the brain under conditions similar to those expected from future AD therapies.